Process for preparing diketone compounds

ABSTRACT

A process for preparing compounds of the formula:                    
     wherein R 2  is lower alkyl; or phenyl optionally substituted by from one to five groups, the same or different, which are lower alkyl, lower haloalkyl, halogen or —SR 4 ; R 3  is halogen, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, —S-alkyl, cycloalkyl having from 3 to 7 carbon atoms in the ring, alkenyl or alkynyl having from 3 to 7 carbon atoms, or -(CR 5 R 6 )—SR 2  wherein q is one or two; R 4  is lower alkyl; R 5  and R 6  independently represent hydrogen, lower alkyl or lower haloalkyl; and n is zero or an integer from one to three; intermediate compounds of the formula:                    
     and processes for preparing them.

This application is the natural phase of PCT/EP97/009370, filed Jan. 28,1997 now WO97/28122.

This invention relates to a process for preparing ketone compounds andthe products obtained by this process. More particularly the inventionrelates to the preparation of intermediate compounds in the manufactureof pesticides.

Pesticidal 4-benzoylisoxazoles, particularly 5-cyclopropylisoxazoleherbicides and intermediate compounds in their synthesis, are describedin the literature, for example in European Patent Publication Nos.0418175, 0487357, 0527036, 0560482, 0609798 and 0682659.

Various methods for preparing these compounds are known. It is an objectof the present invention to provide improved methods for the preparationof these compounds and the intermediate compounds X thereto.

According to one aspect of the invention there is provided a process forthe preparation of a compound of formula (I) by the reaction of acompound of formula (II) with a compound of formula (III), according tothe reaction scheme Sc1 indicated below:

wherein

R₁ is lower alkyl;

R₂ is lower alkyl; or phenyl optionally substituted by from one to fivegroups which may be the same or different selected from lower alkyl,lower haloalkyl, halogen and —SR₄;

R₃ is halogen, lower alkyl, lower haloalkyl, lower alkoxy, lowerhaloalkoxy, —S-alkyl, cycloalkyl having from 3 to 7 ring carbon atoms,alkenyl or alkynyl having from 3 to 7 carbon atoms, or -(CR₅R₆)_(q)—SR₂wherein q is one or two;

n is zero or an integer from one to three;

R₄ is lower alkyl;

and R₅ and R₆ independently represent hydrogen, lower alkyl or lowerhaloalkyl.

The compounds of formula (I) and a number of processes for theirpreparation have been described in the European Patent Applicationscited above.

By the term “lower” is meant radicals comprising at least onehydrocarbon chain, it being understood that such radicals contain fromone to six carbon atoms linked together in a straight- orbranched-carbon chain

Preferably R₁ and R₂ are lower alkyl (most preferably methyl).

Preferably the group —SR₂ occupies the 2-, 3- or 4-position of thephenyl ring (most preferably the 2-position).

Preferably n is one or two.

The reaction generally proceeds in better yield when a group R₃ is nothalogen in the 2-position of the phenyl ring. preferably R₃ is halogenor trifluoromethyl. More preferably (R₃)_(n) is 4-CF₃ or 3,4-dichloro.

The compounds of formula (III) above are known in the literature andtheir preparation has been expressly described in the prior art known tothe skilled worker. Some references particularly pertinent to thepreparation of this reagent may be found by the skilled worker invarious sources of chemical literature. including Chemical Abstracts andinformation databases available to the public.

The preparation of compounds of formula (I) using compounds of formula(II) and (III) according to scheme Sc1 above may be preferably affectedin apolar or apolar aprotic solvent Examples of polar aprotic solventsinclude dimethyl sulphoxide, dimethyl formamide, N,N-dimethylacetamide,N-methyl pyrrolidone, a compound of formula (III); an ether compound,particularly dioxane and tetrahydrofiia; or an aromatic or aliphatichalogenated hydrocarbon, particularly chlorobenzenes. Examples of apolaraprotic solvents include aromatic or aliphatic hydrocarbons,particularly toluene and xylenes.

Generally the reaction temperature used in Sc1above is from 0° C. to theboiling point of the solvent, preferably between 0° C. and 100° C.

Generally the reaction takes place in the presence of a strong basewhich is most preferably selected from an alkoxide of an alkali oralkaline earth metal, notably sodium ethoxide, sodium methoxide, sodiumor potassium t-butoxide; and a metal hydride (notably sodium-hydride).

According to a preferred variant of the process of the present inventionthe reaction is performed with continuous distillation of the alcoholR₁—OH formed in the course of the reaction. at atmospheric pressure orunder reduced pressure (preferably from 1 to 20% below atmosphericpressure). Optionally the alcohol R₁—OH formed may be removed by the useof a suitable molecular sieve for example 4 Angstrom molecular sieve.

According to a further aspect of the present invention there is provideda process for the preparation of a compound of formula (II) by thereaction of a compound of formula (V) with a mercaptan of formula (IV),optionally present in the form of the thiolate, according to reactionscheme Sc2 indicated below:

wherein R₂, R₃ and n in formulae (II) and (V) have the same meanings asgiven before in reaction scheme Sc1. The group —NO₂, is generallypresent in the 2- or 4-position, preferably the 2-position of the phenylring.

Compounds of formula HSR₂ are known in the literature and theirpreparations are expressly described in the prior art known to theskilled worker. The references particularly pertinent to the preparationof this reagent may be found by the skilled worker in various sources ofclassical chemistry including Chemical Abstracts and informationdatabaes available to the public. The salts or thiolates derived fromthe compound of formula (IV) may be prepared by means known to theskilled worker. These thiolates are preferably alkine salts,particularly sodium or potassium thiolate.

The preparation of compounds of formula (II) according to scheme Sc2from the acetophenone of formula (V) and a compound of formula (IV) ispreferably performed in a solvent of the compound of formula (IV) whichmay be inert to the reaction conditions. Examples of other suitablesolvents include sulphoxides such as dimetbyl sulphoxide; amides such asdimethyl formamide. N,N-dimethylacetamide and N-methyl pyrrolidone;ketones such as acetone and methyl isobutyl ketone; ether solvents,particularly dioxane and tetmhydroflran; aromatic, aliphatic andcycloaliphatic hydrocarbons and halogenated or non-halogenatedhydrocarbons, particularly chlorobenzene, dichloromethane and toluene.The presence of a small quantity of water is also acceptable in allowingthe solubilization of the thiolate.

When the reaction according to scheme Sc2 takes place using a compoundof formula (IV) in the form of the mercaptan and not in the form of athiolate salt, the reaction is preferably affected in the presence of abase such as a hydroxide of an alkali metal or alkali earth metal(preferably sodium or potassium), or a carbonate or hydride (such assodium hydride). The reaction may also be performed using various formsof catalyst, particularly phase transfer catalysts such as a quaternaryammonium salt for example tetrabutylammonium bromide.

According to a further aspect of the invention there is provided aprocess for the preparation of a compound of formula (V) by the reactionof a compound of formula (VII) or (VI) as well as a process for thepreparation of a compound of formula (VI) from a compound of formula(VI), according to the reaction scheme Sc3 indicated below:

wherein R₃ and n have the same meanings as in reaction schemes Sc2 andSc1, and X represents halogen, preferably chlorine or fluorine.Preferably the group —NO₂ in formula (VII) is in the 2- or 4-position,most preferably in the 2-position of the phenyl ring.

These two reactions comprise together the reaction scheme Sc3 above andare generally distinct but preferably they may occur in succession Thatis, the compounds of formula (V) may be prepared from the compounds offormula (VII) via an intermediate of formula (VI) which may be isolatedor used in situ in the course of the reaction.

The reaction conditions for the preparation of the compound of formula(V) from the compound of formula (VI) is known in the art and describedin the literature. notably by J. G. Reid and J. M. Reny Runge inTetrahedron Letters, Vol.31 (1990) pp 1093-1096; G. A. Olah et al,Synthesis (1980) pp 662-663; N. Komblum et al, J.Org.Chem., Vol.47(1982) pp 4534-38; S.Chandrasekaran et al, Synthetic Communications,Vol.17 (19807) pp 195-201.

The invention is thus also concerned with the preparation of compoundsof formula (VI) from compounds of formula (VII) by the reaction ofnitroethane in the presence of a base in a solvent which is selectedfrom a compound of formula (VII), nitroethane, a solvent inert to thereaction conditions, and the base being selected from an hydroxide, acarbonate, a hydride, an alkoxide of an alkaline metal or an alkalineearth metal, and guanidine. An advantage of this aspect of the presentinvention is that relatively simple bases may be used in the reactionscheme Sc3.

Solvents suitable for use include nitroethane itself (used in excesscompared to the quantity normally used as a reactant); aromatic oraliphatic halogenated or non-halogenated hydrocarbons, particularlychlorobenzene; aromatic or aliphatic hydrocarbons, particularly tolueneand xylenes; polar aprotic solvents such as dimethyl sulphoxide,dimethyl formamide. N,N-dimethylacetamide, N-methyl pyrrolidone;acetonitrile; ether solvents, particularly dioxane and tetrahydrofuran.The presence of a small quantity of water is also acceptable in allowingthe solubilization of the reaction mixture, while not reacting with thereactants themselves.

The reaction temperature is generally from 0° C. to 50° C. The reactionmay also be carried out in an aqueous or non-aqueous medium. Among thebases suitable for the use in this process one may cite hydroxides orcarbonates of alkali metals or alkaline earth metals preferably sodiumor potassium, sodium carbonate, potassium carbonate or caesiumcarbonate; or tetramethylguanidine. These bases may be used alone or inmixture with others. The reaction may also be conveniently performedusing various types of catalyst, particularly phase transfer catalystssuch as a quartenmy ammonium salt, for example tetrabutylammoniumbromide.

Certain intermediate compounds of formula (II) are novel and as suchconstitute a further feature of the present invention. in particular2-methylthio-4-ftrifluoromethylacetophenone and 3,4-dichloro-2(methylthio)acetophenone.

The following non-limiting examples illustrate the invention

EXAMPLE 1 Preparation of1-cyclopropyl-3-(2-methylthio-4-trifluoromethylphenyl)propne-1,3-dione(reaction scheme Sc1)

In reaction vessel under an inert atmosphere one adds 1.15 g of sodiummethoxide and 22 ml of toluene. This is heated to 80° C. at a pressureof 400 mbars. A mixture of 3.3 ml of methyl cyclopropylcarboxylate and3.8 g of 2-methylthio-4 ftrifluoromethylacetophenone in 6 ml ofanhydrous toluene is added ov 3 hours with constant distillation ofmethanol formed. The reaction is stirred for one hour at 80° C. Thereaction is then cooled and the diketone precipitated in a mixture of 80ml of ice water containing 0.75 ml of concentrated sulphuric acid. Theorganic phase is retained, washed with water and the toluene removedunder reduced pressure to give 3.67 g of 1-cyclopropyl-3-(2-methylthio-4trifluoromethylphenyl)propane-1,3-dione in the form of an or powder,m.p. 64° C. Yield=75%.

By proceeding in a similar manner way heating at a temperature of 70° C.and a pressure of 230 mbars)3-(4-chloro-2-methylthiophenyl)-1cyclopropylpropan-1,3-dione wasprepared in 98% yield (purity greater than 80%). This compound was alsosimilarly prepared wherein the reaction took place at a temperate of 700for 6.5 hours and in the presence of 4 Angstrom molecular sieves inplace of constant distillation of the methanol formed.

EXAMPLE 2 Preparation of1-clopropyl-3-[3,4-dichloro-2-(methylthio)phenyl]propane-1,3-dione(reaction scheme Sc1).

Sodium hydride (0.178 g, 60% oil dispersion. 0.0045 M) is suspended intetrahydrofuran(1.8 ml), stirred and heated at reflux while a solutionof a mixture of methyl cyclopropanecarboxylate (0.42 g, 0.0042M) and3,4-dichloro-2-(methylthio)acetophenone (0.5 g, 0.0021M) intetmhydrofian (3 ml) is added. The mixture is sired and heated at refluxfor 3.5 hours then cooled and poured onto saturated aqueous sodiumbicarbonate. The mixture is then extracted with ether, washed withbrine, dried over magnesium sulphate, filtered and evaporated to give agum which is purified by dry column flash chromatography eluted withethyl acetate in cyclohexane to give3-cyclopropyl-1-[3,4-dichloro-2-(methylthio)phenyl]propane-1,3-dione(0.35 g, 55%) as a yellow oil.

EXAMPLE 3 Preparation of 2-methylthio-4-ftrifluoromethylacetophenone(reaction scheme Sc2).

To 0.15 of 2-nitro-4-trifluoromethvlacetophenone diluted in 0.5 ml ofacetone is added 0.256 g of an aqueous solution of 21% wt/wt sodiumthiomethoxide and the mixture is stirred for five hours at 20° C. Theaqueous phase is separated then removed, 2 ml of water are added and theacetone removed under reduced pressure. The mixture is then treated withdichloromethane and the aqueous phase removed. The organic phase iswashed with fresh water then the solvent is evaporated under reducepressure to obtain 0.085 g of 2-methylthio 4-trifluoromethylacetophenonewith a melting point of 71° C.

By proceeding in a similar manner 3,4-dichloro2-(methylthio)acetophenonemay be prepared, ¹H NMR (CDCl₃) 2.4(s,3H), 2.6(s,3H), 7.15(d,1H), 7.5(d,1H).

EXAMPLE 4 Preparation of1-(2-nitro-4-trifluoromethylphenyl)-1-nitroethane (Reaction Scheme Sc3).

0.87 g of sodium carbonate in 5 ml of anhydrous toluene are placed in a30 ml reaction vessel, and 0.11 g of benzyltnethylamronium chloride and1.13 g of 4-chloro-3-nitro-benzotifluoride and 0.38 g of nitroedhame areadded at the same time. The mix is sired for 16 hours at 20° C., 10 mlof water is added and the aqueous phase is separated then acidified by a4N solution of sulphuric acid. It is then extracted with 5 ml of methylt-butyl ether. After removing the organic solvent 0.18 g of a mixture isobtained which is separated by column chromatography using reverse phasesilica eluting with a mixture of water and acetonitrile to obtain 0.12 gof the title compound, m.p. 48° C.

What is claimed is:
 1. A process for the preparation of a compound offormula (I) by reacting a compound of formula (II) with a compound offormula (III), according to the reaction scheme indicated below:

wherein: R₁ is lower alkyl; R₂ is lower alkyl; or phenyl which isunsubstituted or is substituted by from one to five groups which are thesame or different selected from the group consisting of lower alkyl,lower haloalkyl, halogen and —SR₄; R₃ is halogen, lower alkyl, lowerhaloalkyl, lower alkoxy, lower haloalkoxy, —S-alkyl, cycloalkyl havingfrom 3 to 7 carbon atoms in the ring, alkenyl or alkynyl having from 3to 7 carbon atoms, or -(CR₅R₆)_(q—SR) ₂ wherein q is one or two; R₄ islower alkyl; R₅ and R₆ independently represent hydrogen, lower alkyl orlower haloalkyl; and n is zero or an integer from one to three; whereinthe reaction is performed in an aprotic solvent, in the presence of astrong base, with continuous distillation of the alcohol R₁—OH formed inthe course of the reaction, at atmospheric pressure or under reducedpressure.
 2. A process according to claim 1 wherein the reaction isperformed at a temperature of from 0° C. to the boiling point of thesolvent.
 3. A process according to claim 2, performed at a temperaturebetween 0° C. and 100° C.
 4. A process according to claim 1, wherein thestrong base is an alkoxide of an alkali or alkaline earth metal or ametal hydride.
 5. A process according to claim 2, wherein the strongbase is an alkoxide of an alkali or alkaline earth metal or a metalhydride.
 6. A process according to claim 1, wherein the reaction isperformed at from 1 to 20% below atmospheric pressure.
 7. A processaccording to claim 2, wherein the reaction is performed at from 1 to 20%below atmospheric pressure.